title: Covert preleukemia driven by MLL gene fusion.
abstract: Acute leukemia is considered to be a two- or multiple-step process. Although there is a considerable knowledge regarding the character of the "first hit," the nature of the "second hit" remains unanswered in most of the cases including leukemias with MLL gene rearrangement. We demonstrate here a striking sequence of events, which include a covert, protracted preleukemic phase characterized by a dominant MLL/FOXO3A clone with intact myeloid differentiation and the subsequent acquisition of a secondary genetic abnormality, leading to overt lymphoblastic leukemia. Backtracking of the secondary acute lymphoblastic leukemia (sALL) with the MLL rearrangement showed no blasts in the bone marrow (BM) during the protracted preleukemic phase. However, at the same time (more than 1 year before the sALL diagnosis) the MLL/FOXO3A was present in up to 90% of BM cells including myeloid lineage, suggesting that the fusion arose in a multipotent progenitor. To identify potential "second hit" precipitating sALL we compared DNA in preleukemic versus fully leukemic samples. The analysis revealed a 10 Mb gain on 19q13.32 in the sALL, absent in the preleukemic specimen. These data provide insight into the dynamics of leukemogenesis in secondary leukemia with MLL rearrangement.
authors.affiliation: Department of Paediatric Haematology and Oncology, Childhood Leukaemia Investigation Prague, Charles University Prague, 2nd Medical School, Czech Republic. jan.zuna@lfmotol.cuni.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Zuna
authors.forename: Tatiana
authors.initials: T
authors.lastname: Burjanivova
authors.forename: Ester
authors.initials: E
authors.lastname: Mejstrikova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Zemanova
authors.forename: Katerina
authors.initials: K
authors.lastname: Muzikova
authors.forename: Claus
authors.initials: C
authors.lastname: Meyer
authors.forename: Sharon W
authors.initials: SW
authors.lastname: Horsley
authors.forename: Lyndal
authors.initials: L
authors.lastname: Kearney
authors.forename: Susan
authors.initials: S
authors.lastname: Colman
authors.forename: Hana
authors.initials: H
authors.lastname: Ptoszkova
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
authors.forename: Ondrej
authors.initials: O
authors.lastname: Hrusak
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D020732:Cytogenetic Analysis; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D050939:Gene Fusion; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D022423:Myeloid Cells / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011289:Preleukemia / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase